Plant and animal proteins generally include twenty "protein" amino acids: glycine, alanine, valine, leucine, isoleucine, lysine, phenylalanine, tryptophan, tyrosine, serine, threonine, cysteine, methionine, arginine, asparagine, aspartic acid, glutamine, glutamic acid, histidine, and proline. Hundreds of other "nonprotein" amino acids exist in nature. Most of the naturally occurring nonprotein amino acids are produced in plants, especially in seeds, in which their concentration may reach very high levels. Wink, M. "Special Nitrogen Metabolism," in Plant Biochemistry, Dey, P. M. and Harborne, J. B., Eds., Academic Press, San Diego, pp. 439-486, 1997; Bell, Biochem. J., 70:617-619 (1958); and Rosenthal and Bell, "Naturally Occurring, Toxic Nonprotein Amino Acids," in Herbivores: Their Interaction with Secondary Plant Metabolites, Rosenthal and Janzen, Eds., Academic Press, New York, pp. 361-363, 1979.
Under normal circumstances, nonprotein amino acids are excluded from the process of protein synthesis in plants and animals. Some nonprotein amino acids, however, can be misincorporated into proteins. This can occur, for example, due to the failure of the ribosomal protein synthesizing mechanisms to discriminate between the nonprotein amino acid and one of the twenty protein amino acids. Such misincorporation has been shown to occur in various species, including bacteria, in which impaired colony growth may ensue. Cowie and Cohen, Biochim. et Biophysica Acta, 26:252-261 (1957); and Butler and Peterson, Aust. J. Biol. Sci. 20:77-86 (1967).
The nonprotein amino acid, canavanine, has been studied as an antineoplastic agent. Kruse and McCoy, Cancer Res., 18:279-282 (1958); Green and Ward, Cancer Res., 43:4180-4182 (1983); Thomas et al., Cancer Res., 46:2898-2903 (1986); and Swaffar et al., Cancer Res., 54:6045-6048 (1994). Canavanine also has been demonstrated to have potent antimetabolic, and in particular, insecticidal, properties. Rosenthal and Bell, "Naturally Occurring, Toxic Nonprotein Amino Acids," in Herbivores: Their Interaction with Secondary Plant Metabolites, Rosenthal and Janzen, Eds., Academic Press, New York, pp. 361-363, 1979.
DL methionine sulfoxide, delta-hydroxylysine hydrochloride, and aminoisobutyric acid have been used to suppress the growth of dry rot fungus and related fungi (Armillaria mellea and Basidiomycete) in the suppression of fungal timber infestation. U.S. Pat. No. 4,481,219, to the National Research Development Corporation. Beta-(3-isoxazolin-5-on-2-yl)-alanine has been shown to exhibit antimycotic activity towards Saccharomyces cerevisiae. Schenk et al., Phytochemistry, Oxford, Pergamon Press, 1991, v. 30(2), pp. 467-470. 2-Amino-3-(2,5-dihydro-5-oxo-4-isoxazolyl) propanoic acid has been reported to have antifungal activity against yeast including Candida albicans in vitro and in vivo in mice, and to have a low toxicity in mice. Hakoda et al., J. Antibiotics, 45:854-860 (1992).
While there have been a few isolated studies of certain activities of nonprotein amino acids, as well as studies identifying numerous different kinds of nonprotein amino acids in plants, for the most part, nonprotein amino acids, and in particular, methods for treating humans or animals therapeutically with nonprotein amino acids, have remained largely unexplored.
The emergence of resistant bacterial organisms poses a serious problem in infectious diseases, despite the availability of a large number of agents used for the prevention or treatment of bacterial infections. This is especially true in the hospital environment, in which outbreaks of highly resistant strains of Acinetobacter, Klebsiella, Serratia, and Staphylococcus aureus, among many others, pose a constant threat. H. Simon, "Antimicrobial chemotherapy," in Scientific American Medicine, Scientific American, Inc., Dale and Federman, Eds., New York, 7:XIV:11, June, 1997; and Levy, N. Engl. J. Med., 338:1376-1378 (1998). The problem of resistance to antimicrobial agents extends to the larger community. Penicillin-resistant Streptococcus pneumoniae are an example. Simberkoff, JAMA, 271:1875-1876 (1994). The inevitability of resistance owing to microbial mutations results in the ongoing need for the development of anti-bacterial therapeutic agents.
Fungal infections remain a serious problem in the management of normal as well as immunologically impaired hosts. In the United States the principal systemic mycotic infections in immunologically competent individuals are histoplasmosis, coccidioimycosis and blastomycosis. A fourth infection, sporotrichosis, usually involves the skin and regional lymphatics, although systemic infection occasionally occurs. Fungal infections in the immunocompromised host have become a major problem because of the widespread use of therapeutic agents that damage the immune system, as in the chemotherapy of solid tumors, hematologic malignancies, autoimmune disease, and transplantation. Fungal infections are also a problem in a host immunocompromised as a result of a disorder, such as acquired immunodeficiency syndrome. The principal systemic or life-threatening fungal infections in immunocompromised hosts are: aspergillosis, candidiasis, cryptococcosis (torulosis), and mucormycosis (especially in individuals with diabetes). An additional infection in the immunocompromised now recognized to be fungal is that caused by Pneumocystis carinii.
Infections caused by dermatophytes or yeasts are treated with topical or oral agents. O'Hanley, "Fungal, Bacterial and Viral Infections of the Skin" in Scientific American Medicine, Scientific American, Inc., Dale and Federman, Eds., New York, 2:VII:4-8, April (1996). In the United States, the principal systemic mycotic infections in immunologically competent individuals are treated with amphotericin B. Rubin, R. H., "Infection in the Immunosuppressed Host," in Scientific American Medicine, Scientific American, Inc., Dale and Federman, Eds., New York, 7:X:1-20, January (1997). Systemically administered antifungal drugs are associated with severe side effects and dangerous toxicity. This is especially true for amphotericin B, the principal agent used in the treatment of serious infections. Although some antifungal agents have been developed, there remains a need for effective antifungal agents with minimal side effects.
Thus, there is a need for the development of compounds which are useful as anti-infective agents. There is a need for methods for treating humans and other animals with anti-infective agents which are effective against a wide variety of pathogenic infectious agents including bacteria, fungi, protozoa, and helminthic agents. There further is a need for compounds and compositions which can be administered via a variety of methods including topically, parenterally, orally, by inhalation and by implantation.